Key Mechanism of Inflammatory Response Leading to Osteolysis Identified

Reaction to Orthopedic Wear Debris Mediated in Part by NALP3 Inflammasome Activation

Lyndsey Burton
Hospital for Special Surgery

Daniel Paget
Hospital for Special Surgery

Nikolaus B. Binder, PhD
Hospital for Special Surgery

Krista Bohnert
Hospital for Special Surgery

Bryan J. Nestor, MD
Associate Attending Orthopaedic Surgeon, Hospital for Special Surgery
Associate Professor in Orthopaedic Surgery, Weill Cornell Medical College

Thomas P. Sculco, MD
Surgeon-in-Chief, Hospital for Special Surgery
Professor of Orthopaedic Surgery, Weill Cornell Medical College

F. Patrick Ross, PhD
Hospital for Special Surgery

Steven R. Goldring, MD

Richard L. Menschel Research Chair, Hospital for Special Surgery
Professor of Medicine, Weill Cornell Medical College

Ed Purdue, PhD

Associate Research Scientist, Hospital for Special Surgery

Director, Osteolysis Research Laboratory, Hospital for Special Surgery

Laura Santambrogio, MD, PhD
Albert Einstein College of Medicine

Standing guard on the front line of the bodys immune system response to potential harmful invaders are specialized cellular watchdogs known as a pattern recognition molecules, or PRMs. Just as their name implies, PRMs are responsible for recognizing whether the chemical patterns of other molecules encountered in the body are friend or foe. When particular PRMs recognize a hostile molecular pattern - like that of a virus or bacteria - the PRMs call for an immune system response to fight the invader.

There are many kinds of PRMs, working together in many ways, not all fully known, but an HSS collaboration, published in the January 2013 issue of the Journal of Orthopedic Research, has made an exciting discovery about a PRM known as the NALP3 inflammasome and how it appears to play a critical role in the early stages of osteolysis.

Osteolysis is an inflammatory condition triggered by the immune system reacting to debris particles that have worn off joint replacement implants. Inflammation builds against the particles as if they were hostile invaders, and the continuing reaction can result in the implant loosening in the joint to the point of failure and having to be replaced during revision surgery.

The study identified NALP3 as the inflammasome that reacts to the wear debris particles, and doing its PRM job, deems the wear debris to be toxins requiring an immune system reaction. The resulting inflammatory response can eventually leads to osteolysis. This discovery that NALP3 initiates the particle-induced inflammatory reactions makes NALP3 a potential target for new drug therapies that could halt the inflammation.

Toxic Particles Activate Pathways

When the body reacts to other disease-inducing particulate matter such as silica, asbestos, and the urate crystals of gout, the immune system is activated through the interleukin 1 beta (IL-1) pathway. Production of IL-1 appears to be triggered by certain PRMs that respond to toxins. The inflammasomes identified as triggering the IL-1 response include NALP3.

Recent orthopedic studies have indicated that reactions to the polymer products and metallic particulates and ions in joint implant wear debris may be activating the same IL-1 pathway that respond to toxins.

Interleukin Signals

Interleukins are cytokines, proteins that signal other proteins to take action. Interleukins are one of the main types of cytokine that signal for inflammation to increase in an immune system response. Interleukin-1 consists of two distinct proteins, one of which is IL-1.  (The other is interleukin 1-alpha.)

When the body needs more IL-1 to signal for an inflammatory response, it makes the cytokines using building block proteins known as precursors. One of the enzymes involved in making IL-1 precursors is called caspase-1.

Another role played by caspase-1 is that it is the sole effector of NALP3. That means NALP3 only has one enzyme regulating its functions and that sole effector is caspase-1.

The HSS collaboration studied IL-1 inflammatory reaction to implant wear debris in cellular cultures of macrophages from mice who were bred to have no capase-1, as well as cultures from wild type mice for control. The team also used cultures of healthy human monocyte cells.

Reaction to Polymer Particles

In a normal immune system reaction to toxic particles, NALP3 would recognize the particles as hostile, causing IL-1 production. The IL-1 cytokines would signal for an immune system response. That expected response would be phagocytosis of the particles.
 
Phagocytosis is an inflammatory process where macrophage cells of the immune system surround a toxic molecule to neutralize the invader and move the hostile out of the body.

The study first examined if the continuing phagocytosis of wear debris particles triggers the chronic inflammation, bone loss, and implant loosening of osteolysis that can eventually require revision surgery.

The human monocyte cell cultures were challenged by polymer particles like those that might wear off a joint implant. The particles are called polymethylmethacrylate or PMMA. The cells engulfed the PMMA particles by phagocytosis, leading to an inflammatory immune system responses characterized by IL-1 production.

The cells from the mice with no capase-1 behaved much differently.

No NALP3, No Inflammation

The calvarial bones of both kinds of mice were challenged by PMMA particles. When studied by micro-CT scans, the calvaria of the wild type mice did show indications of the inflammatory response of developing osteolysis. The mice with no capase-1 did not show the same level of inflammatory response, and Micro-CT scans revealed lmuch less osteolysis.

With no capase-1 to act on IL-1 precursors, the caspase-deficient mice were unable to mount an inflammation response triggering levels of IL-1 cytokines. Without the cytokine signaling, inflammatory osteolysis did not happen. Thus, the mice deficient in capsase-1 did not develop the tell-tale signs of developing osteolysis.

Since capase-1 is the sole effector of NALP3, without capase-1, the inflammasome could not accomplish its PRM job. NALP3 was not recognizing the PMMA particles as toxins.. NALP3 was shown as required for the kind of inflammatory immune system response to wear debris-type particles that leads to osteolysis.

Bone Loss Not Connected

The research team also wanted to see if the PMMA particles affected the cellular processes of bone loss.

New bone in a healthy skeleton is created by a complex balancing act involving old bone being removed and new bone cells developing from stem cells in the bone marrow. The old bone is broken down and carried away by specialized cells called osteoclasts.

While the bones of the capase-1 deficient mice showed less osteoclast formation than the bones of the wild type mice, tests did not indicate that these differences were capase-1 dependent. Instead, it seemed likely that less inflammatory reaction in the capase-1 deficient mice helped prevent increased osteoclast production.

Important Osteolysis Study

Few academic institutions have a dedicated program of osteolysis research to match that at HSS, where the Osteolysis Research Laboratory is directed by Associate Scientist Ed Purdue, PhD. Frequent collaborators at the lab include HSS Chief Scientific Officer Steven R. Goldring, MD, and Surgeon-in-Chief Thomas P. Sculco, MD, both of whom worked with Dr. Purdue and others on the NALP3 study.

Recently, the lab identified key components in the end life of bone. They are also involved in pioneering the use of nano-particles to deliver medicines that could treat osteolysis.


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